In the phase III POUT trial, reported in The Lancet, Alison Birtle, MD, and colleagues found that adjuvant gemcitabine/platinum chemotherapy was associated with improved disease-free survival vs surveillance in patients with locally advanced urothelial carcinoma of the upper urinary tract.

Alison Birtle, MD

As stated by the investigators, “No international consensus [currently] exists on the benefit of adjuvant chemotherapy for patients with urothelial carcinoma of the upper urinary tract after nephroureterectomy with curative intent.”

Study Details

In the open-label multicenter trial, 260 eligible patients staged with either muscle-invasive (pT2–pT4, any N) or lymph node–positive (any pT, N1–3) metastasis-free (M0) disease with predominantly transitional cell carcinoma histology after nephroureterectomy were randomly assigned between June 2012 and November 2017 to chemotherapy initiated within 90 days after surgery (n = 131) or surveillance (n = 129).

Chemotherapy consisted of four 21-day cycles of either cisplatin at 70 mg/m² or, for patients with glomerular filtration rate < 50 mL/min only, carboplatin area under the curve = 4.5/5 on day 1 plus gemcitabine at 1,000 mg/m² on days 1 and 8. The primary endpoint was disease-free survival in the intention-to-treat population.

Disease-Free Survival

A preplanned interim analysis met the efficacy criterion for early trial closure. At a median follow-up of 30.3 months, chemotherapy was associated with significantly improved disease-free survival (hazard ratio [HR] = 0.45, 95% confidence interval [CI] = 0.30–0.68, P = .0001). Disease-free survival was 71% vs 46% at 3 years, and median disease-free survival was not reached vs 29.8 months.

Chemotherapy was associated with reduced risk of metastasis or death (HR = 0.48, P = .0007; 3-year event-free rates of 71% vs 53%). Overall survival data were immature at time of analysis; overall, death had occurred in 24 patients in the chemotherapy group and 38 in the surveillance group.

Adverse Events

Grade ≥ 3 adverse events occurred in 44% of the chemotherapy group and 4% of the surveillance group. The most common in the chemotherapy group included decreased neutrophils (36%), decreased platelets (10%), nausea (6%), febrile neutropenia (6%), and vomiting (6%). Serious adverse events were reported in 32% of the chemotherapy group. No treatment-related deaths were reported.

The investigators concluded, “Gemcitabine/platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced urothelial carcinoma of the upper urinary tract. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.”

Dr. Birtle, of Rosemere Cancer Centre, Royal Preston Hospital, Preston, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Cancer Research UK. For full disclosures of the study authors, visit thelancet.com.